Process of preparing codeinone, dihydrocodeinone, and dihydromorphinone



Patented Oct. 6, 1953 PROCESS OF PREPARI HYDROCODEINONE,

PHIN ONE August H. Homeyer, B. De La Mater,

NG CODEINONE, DI- AND DIHYDROMOR- Webster Groves, and George St. Louis County, Mo., assignors to Mallinckrodt Chemical Works, St. Louis, Mo., a corporation of Missouri No Drawing. Application October 20, 1949, Serial No. 122,587

11 Claims.

This invention relates to the production of narcotics and more particularly to a process for the manufacture of morphine derivatives.

This application is a continuation-in-part of our copending application Serial No. 76,855, filed able value for the alleviation of coughs, being more active than codeine in this respect. Until now, dihydrocodeinone has been obtained principally by the catalytic hydrogenation of the naturally occurring opium alkaloid thebaine, but

February 16, 1949, now abandoned. supplies of this natural alkaloid are limited and Briefly this invention provides an effective a satisfactory and economical synthesis from a method for the preparation of dihydrocodeinone more readily obtainable starting material has not from dihydrocodeine, of codeinone from codeine been available. and of dihydromorphinone from dihydromor- Codeine on the other hand is readily availphine by oxidation with a ketone in the presence able and can be converted to dihydrocodeine alof an aluminum alkoxide. most quan i a iv y y catalytic hydrogenation, Among the objects of this invention are the but the known methods for effecting the transprovision of an improved process for the manuformation of dihydrocodeine to dihydrocodeinone facture of morphine derivatives such as dihydrog ve very p0 1" yields and the p s es a e b set codeinone, dihydromorphinone and codeinone; with so many difficulties as to be impracticable. the provision of a process of the type set forth Similar problems are encountered in the prowhich employs readily available starting'mateduction of codeinone and dihydromorphinone. rials; the provision of a process of the type re- Although these are valuable pharmaceuticals a ferred to which gives good yields of dihydro- 2O satisfactory method for the production of cocodeinone, dihydromorphinone or codeinone deinone from codeine and dihydromorphinone without simultaneous formation of substantial from dihydromorphine has not been available. amounts of accompanying by-products; and the We have discovered that if the oxidation of provision of a process of the type indicated which dihydrocodeine to dihydrocodeinone, of codeine permits the recovery of unreacted starting mato codeinone and of dihydromorphine to dihyterial from the reaction mixture. Other objects dromorphinone is effected by certain ketones in will be in part apparent and in part pointed out the presence of aluminum alkoxides, dihydrohereinafter. codeine, codeine and dihydromorphine can be The invention accordingly comprises the steps converted respectively to dihydrocodeinone, coand sequence of steps, and features of manipula- 3U deinone and dihydromorphinone in good yield. tion, which will be exemplified in the methods The unoxidized dihydrocodeine, codeine or dihyhereinafter described, and the scope of the apdromorphine can be conveniently and substanplication of which will be indicated in the followtially completely r cove e t making the v ing claim, all conversion virtually complete.

Dihydrocodeinone is a starting material in the The reactions are represented by the following manufacture of the valuable new analgesic drug equations:

CHaN- OHaN- ore-N- Hg R200 h M R 2 Pd 2 AKOR)! CHaO H Hi0 OH C HsO \O O O O OHPN 0H3 N- 2 AKOR): H2O OH H1O \0 CHaN CHa N- 0H3N Ha RzCO M Pd A1(OR)a H EH H )QOH H 0 o o o metopon, and is itself an analgesic of considerwhere R and R are organic residues.

For this reaction, a ketone having a sufiiciently high oxidation potential is necessary, but the ketone must not contain other functional groups which will destroy or condense with dihydrocodeinone, dihydrocodeine, codeine, codeinone, dihydromorphinone or dihydromorphine. n Quinone, for example, possesses a very high oxidation potential, but when it was used as the oxidizing agent in these reactions, the product was a dark, insoluble substance from which no oxidized product could be isolated. It has been found that cyclohexanone and alkoxy cyclohexanones are capable of oxidizing dihydrocodeine, dihydromorphine and codeine without simultaneous formation of troublesome by-products. Mixtures of such cyclohexanones may likewise be employed. V

While man aluminum alkoxides will serve in this reaction, those alkoxides derived from alcohols which are not themselves oxidized under the conditions of this reaction are preferred. Such alkoxides are the aluminum tertiary alkoxides.

If the aluminum alkoxide is not freshly prepared or if an excess of it is used, it has been found that the unreacted dihydrocodeine is transformed to its stereoisomer, dihydroisocodeine, without affecting the quality or yield of the desired ketone. This does not afiect the over-all conversion to dihydrocodeinone, since the isomer is oxidized under the same conditions as dihydrocodeine itself. If dihydrocodeine is reacted with an aluminum alkoxide without the ketone, it is substantially converted to dihydroisocodeine. This is a simple and convenient method for preparing the latter compound which heretofore could be prepared only by involved and difficult procedures. Dihydroisocodeine is an analgesic which, so far as is known, possesses properties generally quite similar to those of dihydrocodeine.

The reaction should be carried out in a suitable solvent. Any of the inert solvents, su'ch as benzene, toluene or xylene, may be employed.

The following examples illustrate specific embodiments of this reaction:

Example 1 In a 250 ml. flask were placed dry toluene (150 ml.),cyclohexanone (15 ml.; 0.145'mol'e) and anhydrous dihydrocodeine g.; 0.0166 mole). Toluene (50 ml.) was distilled from the flask through a short column and to the resulting clear solution in the flask was added aluminum tertiary-butoxide (2 g.; 0.0081 mole). The resulting mixture was heated under reflux for 17 hours.

The turbid solution was cooled and shaken with 50 ml. of a saturated aqueous solution of potassium sodium tartrate (Rochelle salt) and after the addition of filter aid (5 g.), the resulting emulsion was filtered through a bed of the filter aid. The pale yellow organic layer was separated and Was extracted with a total of 50 ml. of 2% aqueous hydrochloric acid. The acid extract was shaken with two 2-0 ml. zene to remove cyclohexanone and then was made alkaline with excess sodium hydroxide. The solution deposited a small amount of oil and upon stirring and scratching a precipitate formed and the initially deposited oil solidified. The solids were removed from the clear liquid by filtration and after washing with water and drying weighed 1.96 g. (39.2%) and melted at 162% 190 C. The mixed melting point with an authentic sample of dihydrocodeinone (M. Pt. 197 C.) was 173-191 C.

portions of ben- The crude dihydrocodeinone was purified by precipitation as the acid tartrate, and decomposition of the salt yielded 1.10 g. (22%) of material melting at 190-197 C.

The caustic mother liquor was extracted with two 15 ml. portions of chloroform which when evaporated to dryness yielded 3.38 g. of a yellow oil, that was shown to be crude d-ihydrocodeine by conversion to an acid tartrate.

Example 2 In a 500 ml. flask were placed anhydrous dihydroco'deine (10 g.; 0.033 mole), a-methoxycyclohexanone (25.6 g.; 0.2 mole), and dry toluene (250 ml.). Toluene (50 ml.) was distilled from the reaction mixture and to the clear solution was added aluminum tertiary-butoxide (1 g.; 0.004 mole). The mixture was then refluxed for 17 hours.

The solution was cooled, shaken with Rochelle salt solution (50 ml.) and filter aid (5 g.) and filtered. The clear, orange organic layer was shaken with 2% hydrochloric acid solution ml.). The aqueous layer was shaken with one 25 ml. portion of chloroform and two 50 ml. portions of ether. The clear aqueous layer was cooled and stirred mechanically and sodium hydroxide was added dropwise. When a permanent turbidity appeared, sodium hydrosulfite (0.1 g.) was added to prevent discoloration and a seed crystal of dihydrocodeinone was added. Deposition of a crystalline product began and the addition of sodium hydroxide was continued until the solution was strongly alkaline to phenolphthalein. The dense, finely crystalline precipitate of crude dihydrocodeinone was filtered off, washed with water and dried. The yield of dihydrocodeinone was 3.75 g. (37%).

Extraction of the alkaline mother liquor with two 30 ml. portions of chloroform, and evaporation of the chloroform extract to dryness yielded 6.64 g. of crude dihydrocodeine.

Example '3 In a 1 liter flask were placed dihydrocodeine (25 g.), methoxycyclohexanone (42.5 ml.), cyclohexanone (35 ml.) and toluene (450 ml.). Toluene (50 ml.) was distilled off and to the remaining solution was added aluminum tertiary-butoxide (10 g.). The mixture was refluxed for two hours, cooled andextracted with a total of 350 ml. of 2% hydrochloric acid. The acid layer was separated and extracted with two 50 ml. portions of chloroform and two 50 ml. portions of ether to remove non-basic organic material. After the addition of a saturated aqueous solution of R0- chelle salt ml), the acidsolution was cooled and stirred and made alkaline by the slow addition of sodium hydroxide, whereupon a crystalline precipitate of dihydrocodeinone was formed. The yield of dihydrocodeinone melting at 182- 191" C. was 16.2 g. (65

Example 4 In a 200 ml. flask were placed dihydroisocodeine (2.37 g.), alpha-methoxycyclohexanone (8 g.) and toluene (75 ml.). Solvent (25 ml.) was distilled off and to the remaining solution was added aluminum tertiary-butoxide (1 g.). The mixture was refluxed for 3 hours, cooled and shaken with a total of 50 ml. of 2% hydrochloric acid. The combined acid layers were extracted with two 10 ml. portions of chloroform and two 20 ml. portions of ether. iSaturated Rochelle salt solution ml.) was added to the acid solution which was then heated on a steam bath to expel ether. The solution was then cooled and stirred and slowly made alkaline, whereupon there was precipitated 1.8 g. ('76 of material which proved to be crude dihydrocodeinone.

Example 5 Dihydromorphine hydrate (10 g.), methoxycyclohexanone (26 ml.) and toluene (250 ml.) were placed in a flask and a part of the toluene (80 ml.) was distilled off. A solution of aluminum tertiary-butoxide (4. g. in 30 ml. toluene) was added over a period of ten minutes and the mixture was then refluxed for two hours. The cooled mixture was shaken with diluted hydrochloric acid (5 ml. concentrated acid and 70 ml. water) and the acid extract was washed with two successive 25-ml. portions of chloroform and two successive 25-ml. portions of ether. A 30% solution of potassium sodium tartrate ml.) was added to the acid extract; the resulting solution was heated to expel ether and then made alkaline with ammonium hydroxide. When the sides of the container were scratched, a crystalline precipitate formed. This precipitate of crude dihydromorphinone was filtered 01? and dried. It weighed 9 g. and melted over a range from 143 C. to over 200 C. The crude product was dissolved in hot 90% alcohol (90 ml.) and an excess of oxalic acid was added. When the solution cooled and the sides of the vessel were scratched, a crystalline acid oxalate salt formed This was filtered off and recrystallized from 90% alcohol. The purified salt was dissolved in water and converted to the free base with ammonium hydroxide. The purified dihydromorphinone weighed 3.4 g. and melted at 2625-263 C. This material and an authentic sample of dihydromorphinone were compared and found to be identical.

Example 6 Dihydromorphine hydrate (10 g.) was treated with cyclohexanone (34 ml.), toluene (250 ml.) and aluminum tertiary-butoxide following the procedure described in Example 5 above, except that the mixture was refluxed for two and one-half hours. Pure dihydromorphinone was obtained.

Example 7 Codeine hydrate g.), toluene (550 ml.) and methoxycyclohexanone (65 ml.) were placed in a flask and toluene (100 ml.) was distilled oiT. Then 60 ml. of a solution of aluminum tertiarybutoxide in toluene (0.15 g. per ml.) was added and the solution was refluxed for two hours. When the catalyst was added the color of the solution changed from a very pale yellow to a deep orange. After the reaction mixture had cooled, it was extracted with 5% sulfuric acid (250 ml.). The acid extract was then washed with two 50-ml. portions of chloroform followed by two 5'0-ml. portions of ether. Next, a aqueous solution of Rochelle salt (100 ml.) was added to the acid solution, and it was made alkaline with sodium hydroxide, whereupon a precipitate formed. After the solution and precipitate stood overnight in an ice-box, the precipitate, which was a mixture of codeinone and codeine, was filtered off and dried. It weighed 23 g. and melted at PIG-176 C. with decomposition. Fifteen grams of this crude material when twice recrystallized from ethyl alcohol yielded 7.5 g. of codeinone melting at 183.3-

183.8 C. with decomposition. More codeinone could be recovered from the mother liquors. The purified codeinone gave an oxime melting at 217-2l8 C., and a picrate melting at 208.6-210.6 with decomposition. Crystallographic comparison of these derivatives with those obtained from codeinone prepared by chromic acid oxidation showed them to be identical, and further proof of the identity of the product was afiorded by its catalytic hydrogenation to dihydrocodeinone melting at 196.5-197.5.

Many variations and modifications of this invention will be apparent to those skilled in the art. For example, the particular aluminum tertiary-alkoxide employed is not critical, aluminum tertiary-butoxide being preferred because of its availability.

Attention is directed to our copending application Serial No. 269,121, filed January 30, 1952. and our Patent 2,628,962.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

We claim:

1. The process for preparing a substance selected from the group consisting of dihydrocodeinone, dihydromorphinone and codeinone which comprises reacting the corresponding hydroxy compound selected from the group consisting of dihydrocodeine, dihydroisocodeine, codeine and dihydromorphine, in the presence of an aluminum tertiary-alkoxide and a solvent, with a ketone from the group consisting of cyclohexanone and alkoxy-substituted cyclohexanones.

2. The process for preparing dihydrocodeinone which comprises reacting dihydrocodeine with cyclohexanone in the presence of an aluminum tertiary-alkoxide and a solvent.

3. The process for preparing dihydrocodeinone which comprises reacting dihydrocodeine with a-methoxycyclohexanone in the presence of an aluminum tertiary-alkoxide and a solvent.

4. The process for preparing dihydrocodeinone which comprises reacting dihydrocodeine with an a-alkoxycyclohexanone in the presence of an aluminum tertiary-alkoxide and a solvent.

5. The process for preparing dihydromorphinone which comprises reacting dihydromorphine with cyclohexanone in the presence of an aluminum tertiary-alkoxide and a solvent.

6. The process for preparing dihydromorphinone which comprises reacting dihydromorphine with a-methoxycyclohexanone in the presence of an aluminum tertiary-alkoxide and a solvent.

'7. The process for preparing dihydromorphinone which comprises reacting dihydromorphine with an a-alkoxycyclohexanone in the presence of an aluminum tertiary-alkoxide and a solvent.

8. The process for preparing codeinone which comprises reacting codeine with a-methoxycy clohexanone in the presence of an aluminum tertiary-alkoxide and a solvent.

9. The method of preparing dihydrocodeinone which comprises reacting dihydrocodeine with cyclohexanone in the presence of aluminum tertiary-butoxide and toluene.

10. The method of preparing dihydrocodeinone which comprises reacting dihydrocodeine with a-methoxycyclohexanone in the presence of aluminum tertiary-butoxide and toluene.

ensues 11. A precess for oxidizing dihydrocodeine to dihydrocodeinone which comprises reactin dihydrocodeine with cyclohexanone and aluminum tertiary-butoxide in an inert, solvent.

AUGUST H. GEORGE B. DE LA MATER.

Number 8 Number Name Date 2,384,335 ()ppenauer Sept. 4, 1945 FOREIGN PATENTS 6 Number Country Date 415,097 Germany June 13, 1925 OTHER REFERENCES Baker 'et 2.1.: J. Am. Chem. 800., vol. 65, pp. 10 1675-1676 (1943). 

1. THE PROCESS FOR PREPARING A SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF DIHYDROCODEINONE, DIHYDROMORPHINONE AND CODEINONE WHICH COMPRISES REACTING THE CORRESPONDING HYDROXY COMPOUND SELECTED FROM THE GROUP CONSISTING OF DIHYDROCODEINE, DIHYDROISOCODEINE, CODEINE AND DIHYDROMORPHINE, IN THE PRESENCE OF AN ALUMINUM TERTIARY-ALKOXIDE AND A SOLVENT, WITH A KETONE FROM THE GROUP CONSISTING OF CYCLOHEXANONE AND ALKOXY-SUBSTITUTED CYCLOHEXANONES. 